衰老是生物体随着年龄增长在分子、细胞、组织和个体等各个层面所发生的系统性的、极难逆转的功能退化。衰老是威胁人类健康的几大疾病如心脑血管疾病、癌症和神经退行性疾病的共同诱因。然而，衰老发生的原因是人类科学探索不曾抵达之高峰。衰老一般被认为是一个不可避免的、随机且不可控的生命现象。 在过去20多年中，衰老的遗传学研究蓬勃发展，从线虫等模式生物中发现了大量的可以调节寿命的基因和环境因素，证明衰老可以被延缓，提示衰老进程并非完全不可控。然而，科学界对衰老过程本身缺乏理解。虽然有一些研究从亚细胞、组织和个体水平描绘了老年生物体中的某些特征，但是缺乏对衰老过程的系统性研究。为了填补这方面的空白，本研究对线虫衰老过程中基因表达的变化进行了系统的定量分析，在此基础上寻找衰老过程中驱动转录组变化的核心转录因子，并进一步探讨衰老起始的时间和衰老有无程序性特征等根本问题。 通过密集时间点采样，本论文着重分析了线虫衰老早期转录组和蛋白质组的动态变化。一方面，通过比较野生型和daf-16缺失突变体线虫的转录组，我发现调控线虫寿命的核心转录因子DAF-16在正常衰老过程中被激活并对转录组重塑起到关键作用，同时DAF-16的激活也限制了正常衰老过程中转录组的整体变异。另一方面，通过分析野生型、长寿的胰岛素信号突变体和生殖腺缺失突变体等5种线虫品系在衰老过程中的转录组和蛋白质组变化，我发现成虫早期有剧烈的基因表达重塑现象。这一现象发生在成虫后一天内，独立于生殖、有异于发育、在5个线虫品系中重复出现，是体细胞内已知最早的分子层面的衰老相关变化，符合程序性变化的一些特征，暗示线虫衰老可能开始于此时。此外，我发现了一系列可以指示衰老进程的标志物蛋白，它们在成虫期间的丰度变化在长寿线虫中趋缓。 本论文揭示衰老进程有序可寻，在分子水平的衰老相关现象远远早于细胞和个体水平，提出了线虫衰老可能始于成虫开始阶段，其进程具有某些程序性特征。 关键词：DAF-16；胰岛素信号通路；衰老过程；蛋白质组；转录组

 Aging is a time-dependent deterioration process that occurs systematically at all levels from molecules, cells, tissues to the whole organism. In human, aging is the common risk factor for all gerontological diseases such as cardiovascular diseases, cancer and neuronal degeneration diseases. The cause of aging is still a mystery. Aging is generally thought to be stochastic, irreversible, and extremely difficult if not impossible to control. Genetic studies of aging have made tremendous progress over the past two decades. A large number of genes and environmental factors that play a role in regulating lifespan have been discovered in model organisms such as C. elegans, and it has become clear that aging could be slowed down, indicating that it is not completely beyond control. However, despite efforts trying to characterize the molecular or organismal features associated with advanced age, there is a lack of systematic understanding of the aging process. In this study, by profiling age-dependent molecular changes in C, elegans in a systematic and quantitative manner, I aimed to identify key transcription factors that drive age-dependent transcriptome changes, and to start to address two fundamental questions in this field—when aging starts and whether aging is programmed. I have analyzed dynamic gene expression changes at both the transcriptome level and the proteome level at high temporal resolution during C. elegans aging. On one hand, through transcriptome analyses of wild-type and daf-16 null mutant worms, I have unraveled an unexpected role of DAF-16 in shaping the aging transcriptome by regulating hundreds of target genes, and I have also found that DAF-16 limits the global transcriptome drift during normal aging. On the other hand, by analyzing the transcriptome and proteome changes during aging using wild-type worms, long-lived insulin signaling mutants and a mutant lacking the germline, I have found a dramatic gene expression remodeling event. It occurs within one day after C. elegans has reached adulthood in all five examined C. elegans strains, is independent of reproduction and is different from gene expression changes associated with development. To our knowledge, this is the earliest age-related changemuch earlier than known age-related changes occurring at the cellular or organismal level,implicating that aging may start from this period. In addition, I have identified a set of protein markers of aging through principal component analysis and linear regression analysis. The abundance changes of these aging markers slowed down in long-lived worms in a temporally scalable manner. In conclusion, this thesis has revealed that there are orderly changes in the aging process. The results show that the molecular signs of aging precede those at the cellular or organismal level, that C. elegans aging starts right after the beginning of adulthood, and that the process of aging has certain features matching those of a programmed process. Key Words: DAF-16; Insulin signaling pathway; Aging process; Proteome; Transcriptome